Recent advances in γ-secretase modulators (GSMs) offer promising therapeutic strategies for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by amyloid plaques and tau tangles. Unlike γ-secretase inhibitors (GSIs), which disrupt Notch signaling and cause severe side effects, GSMs selectively modulate γ-secretase to reduce toxic amyloid-beta (Aβ42) peptides while increasing nontoxic variants like Aβ37 and Aβ38. Cryo-electron microscopy studies have helped elucidate the structural basis of γ-secretase function, revealing mechanisms of substrate recognition and drug binding. Pfizer’s PF-06648671 and Roche’s RG6289 have advanced into clinical trials, showing robust Aβ42-lowering effects and favorable tolerability in Phase 1 clinical trials. GSMs have the potential to serve as a primary prevention method for Alzheimer’s disease or as a maintenance therapy to sustain the benefits achieved through amyloid clearance with anti-Aβ antibodies. Despite progress, challenges remain in optimizing GSMs for improved potency, safety, and drug-like properties. Structural insights into GSM binding and substrate processing continue to guide rational drug design. This chapter highlights the development, mechanisms, and therapeutic potential of GSMs, emphasizing their role as safer alternatives to GSIs for AD treatment and prevention.